Project Summary There are over 5 million people in the US currently living with Alzheimer's Disease (AD). Despite the loss of life, deterioration in quality of life, and social and financial costs of this devastating disease, there is still no cure or effective treatment to slow disease progression. A variety of approaches show promise in defining the key molecular changes that underlie pathology in AD. Many of these studies focus on the microtubule associated protein Tau and understanding how Tau contributes to neurodegeneration. A genetic screen for modulators of Tau pathology in C. elegans identified Suppressor of Tau 2 (sut-2). The sut-2 protein is a member of an evolutionarily-conserved family of nuclear, zinc finger polyadenosine RNA binding proteins. The human protein is termed Zinc Finger Cys3 His #14 (ZC3H14) or MSUT2. In our preliminary studies, we have identified ZC3H14 enriched in insoluble aggregates in AD brain. Furthermore, we have identified physical interactions between murine ZC3H14 and components of the RNA spliceosome including the U1-70K protein, which the Seyfried laboratory has linked to Tau pathology. Finally, ZC3H14 binds to the Mapt transcript encoding Tau suggesting a role for ZC3H14 in modulating post-transcriptional processing and/or expression of Tau. Based on our preliminary data and the discovery of sut-2 as a Tau modifier, we hypothesize that ZC3H14 interacts with critical RNA binding proteins and contributes to Tau-mediated pathology. Drawing extensively on resources available in the Alzheimer's Disease Research Center (ADRC) at Emory and our own preliminary data, we propose a collaborative multi-PI (Corbett and Seyfried) approach to test our hypothesis through the following specific aims: Aim 1) Define the spectrum of ZC3H14-interacting proteins in normal and AD brain; and Aim 2) Assess whether a decrease in ZC3H14 levels ameliorates Tau-induced pathology in a mouse model of Tau-mediated pathology and probe potential mechanisms. Our collaborative team is uniquely qualified to perform the proposed studies as 1) we have access to the required patient samples and expertise in proteomics provided by the Emory Proteomics core directed by MPI Seyfried; and 2) we have created the first Zc3h14 (MSUT2) knockout mouse. The homozygous Zc3h14 null (Zc3h14-/-) mice are viable and fertile and available to cross to Tau P301S transgenic mice (Line PS19) to assess whether ZC3H14 modifies Tau phenotypes in mammals. In addition, we will exploit these mice for preliminary analysis of how ZC3H14 regulates Tau expression. The goal of this exploratory proposal is to probe the mechanism by which ZC3H14 contributes to Tau-induced pathology. The long-term goal of our studies is to identify molecular pathways that could be targeted to modulate Tau-induced pathology.